Peripheral and Central Interactions in Energy Balance (Barbara B. Kahn, MD, Principal Investigator, Beth Israel Deaconess Medical Center). Obesity and related disorders such as Type 2 diabetes mellitus are major healthcare issues in the United States, and decreasing their incidence in adults and children would have profound social and economic ramifications. For this to occur, an increased understanding of the mechanisms controlling food intake and body weight is essential. There has been tremendous recent progress in elucidating critical metabolic signals and the oathways in the brain and in peripheral tissues in which these signals act. In the past grant period the projects in this orogram investigated the central and peripheral actions of leptin. This included the neural pathways activated by leptin and the cellular pathways engaged by leptin in the CMS and skeletal muscle. We also examined the effects of manipulation of leptin receptors in specific neuronal cell groups on energy homeostasis. We offer 5 individual proposals that utilize state of the art genetic, physiological, biochemical, and neuroanatomic techniques to investigate the actions of critical metabolic cues including leptin, ghrelin, and nutrient sensing in the regulation of food intake, energy expenditure, and body weight. These studies will extend from molecular mechanisms of action to systems based studies to understand the physiological importance of these hormones through specific neural circuits. Our proposal consists of 5 individual projects and 3 cores. Project 1 will use functional neuroanatomy to assess the hypothesis that the recently identified hormone ghrelin acts through similar pathways as leptin. Studies will critically test the role of AGRP/NPY neurons in mediating the important actions of ghrelin by generating and evaluating mice that express ghrelin receptors exclusively on AGRP/NPY neurons. Project 2 will assess the role of melanin concentrating hormone (MCH) in regulating energy expenditure through effects on sympathetic activity and resting energy expenditure and through effects on the dopamine system locomotor activity. Project 3 focuses exclusively on the arcuate nucleus (AGRP/NPY neurons and POMC neurons) and uses genetically engineered mice to test specific hypotheses regarding the role of two afferent signals, leptin (new Aim #1) and "lipid sensing" (new Aim #2), and two efferent signals, glutamate and GABA (new Aim #3) in regulating energy homeostasis. Project 4 will assess the biologic significance of the AMP-activated protein kinase (AMPK) pathway in mediating the central and peripheral effects of leptin on energy homeostasis. This will include determining if impaired leptin action on AMPK contributes to "leptin resistance" in obesity; how the AMPK pathway integrates with other leptin signaling pathways; and which neuronal circuits mediate the effects of AMPK on food intake and energy homeostasis. Project 5 will examine the role of suppressor of cytokine signaling 3 (SOCS3) in the neuronal actions of both leptin and insulin. This will involve studies of leptin and insulin signaling and physiologic actions in mice with generalized neuronal deletion of SOCS3, and deletion or overexpression of SOCS3 in AgRP and POMC neurons. Core A will be an administrative core. Core B will be a Neuroanatomy Core and Core C will be a Physiology Core. Together, these projects will continue to leverage the collaborative efforts and expertise of investigators in Boston and will greatly increase the understanding of the central circuits regulating body weight.